RNA-binding proteins in atherosclerosis

项目摘要/摘要 胆固醇稳态的紊乱是心血管疾病的主要诱因，并与 合并症。这项建议的目的是确定RNA结合蛋白在胆固醇中的作用 代谢和动脉粥样硬化。RNA结合蛋白和非编码RNA之间的相互作用可能会影响 特定遗传邮政编码的转录输出，无论是局部的还是跨多条染色体的。 进一步强调这一前提的是，我们的初步研究表明，转录辅助激活因子和RNA结合 Raly蛋白与非编码RNA Lexis相互作用调节胆固醇生物合成的表达 基因。利用这一新的见解，我们的目标是研究RALY在固醇代谢中的作用。 在目标1中，我们定义了Raly在胆固醇代谢中的生理作用以及在动脉粥样硬化中的作用。 发展。我们将通过研究组织特异性缺失Raly的小鼠或小鼠来验证假设 用增强型或失调型腺病毒载体转导。在目标2中，我们将通过以下方式来研究这些机制 哪种RALY会影响基因表达。利用无偏见的全基因组方法将绘制潜在的Raly 结合部位及其对染色质结构的影响并破译其协作和等级关系 带有转录调节剂。这些研究有望从根本上深入了解机制。 控制代谢调节，同时探索治疗干预的新机会。

PROJECT SUMMARY/ABSTRACT Perturbations in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The objective of this proposal is to define the role of RNA-binding proteins in cholesterol metabolism and atherosclerosis. Interactions between RNA-binding proteins and non-coding RNAs may affect transcriptional outputs at specific genetic zip codes, either locally or across multiple chromosomes. Reinforcing this premise, our preliminary studies suggest that the transcriptional coactivator and RNA-binding protein Raly interacts with the noncoding RNA LeXis to modulate the expression of cholesterol biosynthetic genes. Capitalizing on this novel insight, we aim to investigate the contributions of RALY in sterol metabolism. In Aim 1, we define the physiologic role of Raly in cholesterol metabolism and contributions to atherosclerosis development. We will test out hypotheses by studying mice with tissue specific deletion of Raly or mice transduced with gain- or loss-of-function adenoviral vectors. In Aim 2, we will investigate the mechanisms by which RALY influences gene expression. Utilizing unbiased genome wide approaches will map potential Raly binding sites, its influence on chromatin architecture and decipher its cooperative and hierarchical relationship with transcriptional modulators. These studies are expected to shed fundamental insight into mechanisms controlling metabolic regulation while exploring novel opportunities for therapeutic intervention.